The ultra-rapidly activating delayed rectifier K+ current (IKur) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, IKur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of IKur, that is a compound which blocks Kv1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III antiarrhythmic agents. (Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression.)
Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma. Although the underlying pathogenesis of each of these conditions may vary, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, lymphocytes recognize the foreign tissue antigens and begin to produce immune mediators which lead to graft rejection or graft-vs-host rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion in which both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
Cyclosporin A, which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA for the prevention of rejection in liver transplantation. Cyclosporin A and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. In 1994, Cyclosporin A was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though these agents are effective in fighting transplant rejection, Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunosuppressant without these side effects still remains to be developed. Potassium channel inhibitors as described here promise to be the solution to this problem, since inhibitors of Kv1.3, for example, are immunosuppressive. See, Wulff et al., “Potassium channels as therapeutic targets for autoimmune disorders,” Curr Opin Drug Discov Devel. 2003 September; 6(5):640-7; Shah et al., “Immunosuppressive effects of a Kv1.3 inhibitor,” Cell Immunol. 2003 February; 221(2):100-6; Hanson et al., “UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation,” Br J Pharmacol. 1999 April; 126(8):1707-16.
Inhibitors of Kv1.5 and other Kv1.x channels stimulate gastrointestinal motility. Thus, the compounds of the invention are believed to be useful in treating motility disorders such as reflux esophagitis. See, Frey et al., “Blocking of cloned and native delayed rectifier K channels from visceral smooth muscles by phencyclidine,” Neurogastroenterol Motil. 2000 December; 12(6):509-16; Hatton et al., “Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal,” J Physiol. 2001 Jun. 1; 533(Pt 2):315-27; Vianna-Jorge et al., “Shaker-type Kv1 channel blockers increase the peristaltic activity of guinea-pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system,” Br J Pharmacol. 2003 January; 138(1):57-62; Koh et al., “Contribution of delayed rectifier potassium currents to the electrical activity of murine colonic smooth muscle,” J. Physiol. 1999 Mar. 1; 515 (Pt 2):475-87.
Inhibitors of Kv1.5 relax pulmonary artery smooth muscle. Thus, the compounds of the invention are believed to be useful in treating hypertension and otherwise improving vascular health. See, Davies et al., “Kv channel subunit expression in rat pulmonary arteries,” Lung. 2001; 179(3):147-61. Epub 2002 Feb. 4; Pozeg et al., “In vivo gene transfer of the O2 -sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats,” Circulation. 2003 Apr. 22; 107(15):2037-44. Epub 2003 Apr. 14.
Inhibitors of Kv1.3 increase insulin sensitivity. Hence, the compounds of the invention are believed to be useful in treating diabetes. See, Xu et al., “The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity,” Proc. Natl. Acad. Sci. U.S.A. 2004 Mar. 2; 101(9):3112-7. Epub 2004 Feb. 23 (epublished 2004 Feb. 23); MacDonald et al., “Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion,” Mol. Endocrinol. 2001 August; 15(8):1423-35; MacDonald et al., “Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets,” Diabetologia. 2003 August; 46(8):1046-62. Epub 2003 Jun. 27.
Stimulation of Kv1.1 is believed to reduce seizure activity by hyperpolarizing neurons. Thus, the compounds of the invention are believed to be useful in treating seizures, including seizures associated with epilepsy and other neurological diseases. See, Rho et al., “Developmental seizure susceptibility of kv1.1 potassium channel knockout mice,” Dev Neurosci. 1999 November; 21(3-5):320-7; Coleman et al., “Subunit composition of Kv1 channels in human CNS,” J Neurochem. 1999 August; 73(2):849-58; Lopantsev et al., “Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1,” Epilepsia. 2003 December; 44(12):1506-12; Wickenden, “Potassium channels as anti-epileptic drug targets,” Neuropharmacology. 2002 December; 43(7): 1055-60.
Inhibition of Kv1.x channels improves cognition in animal models. Thus, the compounds of the invention are believed to be useful in improving cognition and/or treating cognitive disorders. See, Cochran et al., “Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage-activated K+-channels,” Eur J. Neurosci. 2001 November; 14(9):1455-63; Kourrich et al., “Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats,” Behav Brain Res. 2001 Apr. 8; 120(1):35-46.